Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension

Only a small percentage of patients with chronic thromboembolic pulmonary hypertension are eligible for pulmonary thrombendarterectomy. We investigated the effects of oral sildenafil on hemodynamics and exercise capacity in 12 nonoperable chronic thromboembolic pulmonary hypertension patients. All patients were in disease progression despite sufficient long-term anticoagulation and the best supportive care and suffered from severe pulmonary hypertension (pulmonary vascular resistance index 1,935 +/- 228 dyn. s. cm-5. m2, cardiac index 2.0 l. min-1. m-2, 6-minute walking distance 312 +/- 30 m). After approximately 6 months of sildenafil treatment, pulmonary hemodynamics and exercise capacity improved significantly (pulmonary vascular resistance index 1,361 +/- 177 L. min-1. m2, p = 0.004, cardiac index 2.4 +/- 0.2 L. min-1. m-2, p = 0.009, 6-minute walking distance 366 +/- 28 m, p = 0.02). Therefore, oral sildenafil may offer a new option for medical treatment of this devastating disease.     

Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension

STUDY OBJECTIVES: We performed an open-label multicenter study to evaluate the safety and efficacy of the dual endothelin receptor antagonist bosentan in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). PATIENTS: Nineteen patients with inoperable CTEPH were enrolled. MEASUREMENTS: The primary end point was a change in pulmonary vascular resistance (PVR). Secondary end points included 6-min walk test, peak oxygen uptake (V(O2)), New York Heart Association functional class, serum levels of N-terminal-pro brain natriuretic peptide (NT-pro-BNP), and various other hemodynamic parameters. RESULTS: After 3 months of treatment with bosentan, PVR decreased from 914 +/- 329 to 611 +/- 220 dyne.s.cm(-5) (p < 0.001). Functional class and peak V(O2) remained unchanged, but 6-min walk distance increased from 340 +/- 102 to 413 +/- 130 m (p = 0.009), and serum NT-pro BNP levels improved from 2,895 +/- 2,620 to 2,179 +/- 2,301 (p = 0.027). One patient died, presumably from influenza A infection, and another patient experienced progressive fluid retention despite reduction of PVR. Other than that, treatment was well tolerated by all patients. CONCLUSIONS: This open-label pilot trial suggests that bosentan may offer a therapeutic option for patients with inoperable CTEPH. Randomized controlled trials are warranted to confirm these findings.     

The efficacy of bosentan in inoperable chronic thromboembolic pulmonary hypertension: a 1-year follow-up study.

The treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). However, many patients develop a severe progressive small vessel pulmonary arteriopathy that is inaccessible to surgical intervention and is associated with poor survival. The purpose of the present study was to evaluate the medium-term efficacy and safety of the dual endothelin receptor antagonist, bosentan, in inoperable CTEPH. Forty-seven patients with inoperable CTEPH (distal disease or persistent pulmonary hypertension following PEA) underwent evaluation after 1 yr of bosentan therapy. Outcomes included assessment of 6-min walk test (6MWT), haemodynamics and World Health Organization functional classification. Monitoring of serious adverse effects and changes in therapy was undertaken. Patients showed sustained improvements in 6MWT (49+/-8 m), functional classification, cardiac index (+0.2+/-0.07 L.min(-1).m(-2)) and total pulmonary resistance (-139+/-42 dyn.s.cm(-5)). Those patients with persisting pulmonary hypertension following PEA showed the greatest improvement. One-yr survival was 96%, and bosentan was well tolerated with only one patient developing deranged liver function. Although all patients with chronic thromboembolic pulmonary hypertension should be considered for pulmonary endarterectomy, bosentan provides an alternative medical therapy to improve function and delay the progression of this devastating disease in those in whom surgery is not suitable.     

Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension

BACKGROUND: There are currently no licensed medical therapies for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: In this double-blind, placebo-controlled pilot study, 19 subjects with inoperable CTEPH were randomly assigned to sildenafil or placebo for 12 weeks. The primary end point was change in 6-min walking distance (6MWD). Secondary end points included changes in World Health Organization (WHO) class, cardiopulmonary hemodynamics, quality of life (QOL) scores, and N-terminal pro brain natriuretic peptide (NT-proBNP). All subjects were transferred to open-label sildenafil at the end of the study and offered repeat assessment at 12 months. RESULTS: There were no significant differences between the two groups with respect to change in exercise capacity. However significant improvements were seen in WHO class and pulmonary vascular resistance (PVR). Seventeen subjects were eligible for reassessment at 12 months and demonstrated significant improvements in 6MWD, activity and symptom components of QOL, cardiac index, PVR, and NT-proBNP. CONCLUSIONS: Although this pilot study was insufficiently powered to test the primary end point, it did suggest beneficial effects in favor of sildenafil in several secondary end points at both 3 months and 12 months. Further larger-scale trials of sildenafil in inoperable CTEPH are required to confirm these findings and potentially increase the treatment options available for this devastating disease. TRIAL REGISTRATION: The study protocol was registered with the UK National Research Register database (publication ID N0542136603).     

Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension

OBJECTIVES: We sought to investigate the impact of adjunct sildenafil on exercise capacity and hemodynamic parameters in patients with pulmonary arterial hypertension (PAH) who fulfilled predefined criteria of deterioration despite ongoing treatment with inhaled iloprost. BACKGROUND: Inhaled iloprost is an effective therapy in PAH. The phosphodiesterase-5 inhibitor sildenafil exerts pulmonary vasodilation and may amplify prostanoid efficacy. METHODS: Of 73 PAH patients receiving long-term inhaled iloprost treatment, 14 fulfilled criteria of deterioration unresponsive to conventional treatment. These patients received adjunct oral sildenafil over a period of nine to 12 months, leaving the inhalative iloprost regimen unchanged. RESULTS: Before iloprost therapy, the baseline 6-min walking distance was 217 +/- 31 m (mean +/- SEM), with an improvement to 305 +/- 28 m within the first three months of iloprost treatment and a subsequent decline to 256 +/- 30 m after 18 +/- 4 months. Adjunct therapy with sildenafil reversed the deterioration and increased the 6-min walk distance to 346 +/- 26 m (p = 0.002, Wilcoxon test) at three months of combined therapy, with a sustained efficacy up to 12 months (349 +/- 32 m, p = 0.002). The distribution of New York Heart Association functional classes (IV/III/II) improved from September 9, 2000, before sildenafil, to January 8, 2003, after nine to 12 months with sildenafil. All hemodynamic variables changed favorably: pulmonary vascular resistance decreased from 2,494 +/- 256 before sildenafil to 1,950 +/- 128 dynes.s.cm(-5).m(2) after three months of adjunct sildenafil (p = 0.036). Two patients died of severe pneumonia during the period of combined therapy. No further serious adverse events occurred. CONCLUSIONS; In patients with severe PAH deteriorating despite ongoing prostanoid treatment, long-term adjunct oral sildenafil improves exercise capacity and pulmonary hemodynamics. A combination of prostanoids and sildenafil is an appealing concept for future treatment of pulmonary hypertension.     

Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension

BACKGROUND: Inhaled treprostinil was recently developed for the treatment of pulmonary arterial hypertension (PAH). We investigated the safety and acute haemodynamic effects of the combination oral sildenafil and inhaled treprostinil in an open label study in patients with precapillary pulmonary hypertension. METHODS AND PATIENTS: Inhaled nitric oxide (20ppm; n=50), sildenafil (50mg; n=50) and inhaled treprostinil (15mug; n=25 or 30mug; n=25) were applied in subsequent order during right heart catheter investigation to consecutive patients with pulmonary arterial hypertension (PAH; n=28), non-operable chronic thromboembolic pulmonary hypertension (CTEPH; n=17) and pulmonary fibrosis associated pulmonary hypertension (n=5). RESULTS: Inhaled nitric oxide reduced pulmonary vascular resistance (PVR) to 87.3+/-5.1% of baseline values, reduced mean pulmonary arterial pressure (PAP) to 89.7+/-3.5% and increased cardiac output (CO) to 102.4+/-2.9%. Sildenafil reduced PVR to 80.1+/-5.0%, mPAP to 86.5+/-2.9% and increased CO to 103.8+/-3.2%. Treprostinil, inhaled 1h after sildenafil, reduced PVR to 66.3+/-3.8%, mPAP to 77.8+/-3.3%, and increased CO to 107.1+/-3.3% (mean+/-95% confidence interval). Subgroup analysis showed similar acute haemodynamic effects in PAH and CTEPH patients. Ventilation/perfusion distribution measurement in six patients with pre-existing gas exchange limitations was not changed by sildenafil and treprostinil. Relevant side effects were not observed. CONCLUSION: The combination of sildenafil and inhaled treprostinil was well tolerated and induced additive, pulmonary selective vasodilatation in pulmonary hypertension patients. This could be of relevance also for long-term treatment of PAH and CTEPH patients.     

Long-term bosentan in chronic thromboembolic pulmonary hypertension

BACKGROUND: There is no approved pharmacological treatment for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are not suitable for pulmonary endarterectomy (PEA). OBJECTIVE: The study investigates the effect of the dual endothelin receptor antagonist bosentan on exercise tolerance (6-min walking distance, 6MWD) and right ventricular function (Tei index) in patients with CTEPH over 24 months. METHODS: Twelve consecutive patients (5 males and 7 females) with CTEPH not eligible for PEA or following partial or complete failure of PEA were included in a non-randomized, open-label prospective study. All patients were WHO class III. They were included, if progressive pulmonary hypertension was diagnosed despite best supportive treatment. Bosentan was started at 62.5 mg b.i.d. and increased to the final dose of 125 mg b.i.d. RESULTS: 6MWD and the Tei index were assessed every 6 months. We observed a significant increase in 6MWD from 319 +/- 85.0 m at baseline to 391 +/- 76.9 m at 6 months and a significant decrease in the Tei index from 0.39 +/- 0.10 at baseline to 0.34 +/- 0.08 at 6 months. This improvement was maintained over 24 months (6 MWD: 381 +/- 101 m; Tei index: 0.31 +/- 0.03). Six patients exhibited an improvement in WHO class at 6, 12 and 18 months, 5 demonstrated improvement at the 24-month follow-up. The remainder were stable throughout the study period. CONCLUSION: This is the first study demonstrating a long-term beneficial effect of bosentan on exercise tolerance (6MWD) and right heart function (Tei index) in CTEPH.     

Clinical efficacy of sildenafil in patients with pulmonary hypertension in functional class II or III

Objective

To assess the efficacy of treatment with sildenafil monotherapy in patients with pulmonary hypertension.

Patients and methods

An observational study was undertaken in 11 patients with pulmonary hypertension in functional class II or III who received treatment with sildenafil (150 mg/day). Seven of the patients had inoperable chronic thromboembolic pulmonary hypertension and 4 had pulmonary arterial hypertension. To assess treatment response, the following parameters were assessed during follow-up at 3, 6, and 12 months: exercise tolerance in the 6-minute walk test, change in functional class, and systolic pulmonary arterial pressure measured by echocardiography.

Results

We observed a significant improvement in exercise tolerance, as shown by increased 6-minute walk distance after 3, 6, and 12 months of treatment (increases of 20, 67, and 95 m, respectively). All patients showed an improvement in functional class. The results of echocardiography did not reveal statistically significant differences in systolic pulmonary arterial pressure between baseline and 6 or 12 months of treatment. No significant adverse effects were observed, although sildenafil treatment was suspended in 1 patient due to persistent headache.

Conclusions

the results of this study confirm that sildenafil is an effective drug for the management of pulmonary arterial hypertension and inoperable chronic thromboembolic pulmonary hypertension both in the short term and medium to long term, and that the drug is well tolerated and shows few side effects.     

Sildenafil improves endothelial function in patients with pulmonary hypertension

BACKGROUND: Sildenafil has been shown to be effective in the treatment of pulmonary hypertension, and has favourable effects on endothelial function. Our hypothesis is that a part of the beneficial effects of sildenafil in patients with pulmonary hypertension is due to the improvement of the endothelial function. METHODS: Nine patients (seven females, age 67+/-9 years) with thromboembolic pulmonary hypertension were treated with sildenafil, at a mean dose of 150+/-75 mg/die. At baseline and after 6 months all patients underwent: right-heart catheterization, 6-min walking distance, and a study of endothelial function, including the measure of the flow-mediated vasodilation of the brachial artery, and the dosage of plasma levels of endothelin-1 and von Willebrand factor. RESULTS: During follow-up we found a significant reduction of mean pulmonary artery pressure and arteriolar resistances. Accordingly, the functional capacity improved (an average of+37 m). Sildenafil improved endothelial-dependent vasodilation and reduced plasma concentrations of endothelin-1 (from 4.5+/-0.6 to 3.1+/-0.7 pg/mL; p<0.0001) and von Willebrand factor (from 183.1+/-10.1 to 149.1+/-17.6 mU/mL; p<0.0001). CONCLUSION: Improvement of the endothelial function may represents one of the mechanisms able to explain the favourable effects sildenafil has shown in patients with pulmonary hypertension.     

Assessment of the vasodilator response in primary pulmonary hypertension. Comparing prostacyclin and iloprost administered by either infusion or inhalation.

AIMS: To directly compare the differential effects of oxygen, prostacyclin and iloprost (aerosolized and intravenous) in primary pulmonary hypertension. METHODS AND RESULTS: Twenty-one patients with severe primary pulmonary hypertension underwent right heart catheterization following oxygen inhalation, inhalation of aerosolized iloprost, intravenous prostacyclin or intravenous iloprost. The stability of the iloprost solution was tested for up to 4 weeks. Oxygen slightly decreased pulmonary vascular resistance. Intravenous prostacyclin (7.2+/-3.4 ng kg(-1) min(-1)) reduced pulmonary (1772+/-844 vs 1325+/-615 dyn s cm(-5), P<0.001) and systemic vascular resistance, and arterial and right atrial pressure, while cardiac output increased. Iloprost inhalation diminished pulmonary (1813+/-827 vs 1323+/-614 dyn s cm(-5), P<0.001) and systemic vascular resistance, and pulmonary artery (58+/-12 vs 50+/-12 mmHg,P<0.001) and right atrial pressure, while cardiac output increased. With intravenous iloprost (1.2+/-0.5 ng kg(-1) min(-1), n=8) a decrease in pulmonary (2202+/-529 vs 1515+/-356 dyn s cm(-5), P<0.05) and systemic vascular resistance and right a trial pressure occurred while cardiac output increased. Iloprost solution remained stable for 33 days while losing <10% (4 degrees C) of its active drug concentration.Conclusions Intravenous iloprost and prostacyclin have very similar haemodynamic profiles. In contrast, only inhaled iloprost exerted selective pulmonary vasodilation, reducing pulmonary vascular resistance and pulmonary artery pressure without systemic vasodilation. The longer half-life and extended stability despite lower costs render iloprost an attractive alternative to chronic prostacyclin treatment in primary pulmonary hypertension.     

Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension

STUDY OBJECTIVES: The aim of this long-term multicenter analysis was to investigate whether subcutaneously infused treprostinil could provide sustained improvements of exercise capacity and survival benefits in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Subcutaneous administration of the prostacyclin analog treprostinil is an effective treatment for PAH that, unlike epoprostenol, does not require the insertion of a permanent central venous catheter. DESIGN: Multicenter retrospective study. SETTING: Three European university hospitals. METHODS: Ninety-nine patients with PAH and 23 patients with CTEPH in New York Heart Association (NYHA) classes II-IV were followed up for a mean of 26.2 +/- 17.2 months (+/- SE) [range, 3 to 57 months]. Long-term efficacy was assessed by 6-min walking distance (SMWD), Borg dyspnea score, and NYHA class. Clinical events were monitored to assess survival and event-free survival. RESULTS: At 3 years, significant improvements from baseline were observed in mean SMWD (305 +/- 11 to 445 +/- 12 m, p = 0.0001), Borg dyspnea score (5.7 +/- 0.2 to 4.5 +/- 1, p = 0.0006), and NYHA class (3.20 +/- 0.04 to 2.1 +/- 0.1, p = 0.0001). These changes were observed under a mean dose of subcutaneously infused treprostinil at 40 +/- 2.6 ng/kg/min (range, 16 to 84 ng/kg/min). Subcutaneously infused treprostinil was well tolerated, and local pain at the subcutaneous site accounted for treatment interruption in only 5% of the cases. Survival was 88.6% and 70.6% at 1 year and 3 years, respectively. At the same time points, the event-free survival rates, defined as survival without hospitalization for clinical worsening, transition to IV epoprostenol, and need for combination therapy or atrial septostomy, were 83.2% and 69%, respectively. CONCLUSIONS: Long-term subcutaneous therapy with treprostinil appears to continuously improve exercise tolerance and symptoms in patients with PAH and inoperable CTEPH. Moreover, treatment may provide a significant survival benefit.     

Thrombo-embolic pulmonary hypertension--do not spoil a chance for effective surgery!

Chronic thromboembolic pulmonary hypertension (CTEPH) can be defined as pulmonary hypertension with persistent pulmonary perfusion defects causes by unresolved thrombi. All symptomatic CTEPH patients with documented pulmonary vascular resistance > 300 dyn*sec*cm(-5) and proximal lesions should be considered for surgical treatment--pulmonary endarterectomy. The role of pharmacological treatment remains controversial and should be restricted to inoperable cases and persistent pulmonary hypertension after pulmonary endarterectomy. Every year about 30 procedures is performed in two specialised centers in Poland with 1 year mortality at 8-9%. Number of procedures done gives the frequency of pulmonary endarterectomy at 0.7/million of population/year. Current data from UK indicate the actual ratio of surgical treatment of CTPH at 2/million/year. The article discusses reasons for CTEPH is underdiagnosed and why rate of surgical therapy in Poland is too low.     

Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients

This retrospective, multicentre study evaluated patients with lymphangioleiomyomatosis (LAM) and pre-capillary pulmonary hypertension (PH) by right heart catheterisation. It was conducted in 20 females with a mean±sd age of 49±12 yrs and a mean±sd time interval between LAM and PH diagnoses of 9.2±9.8 yrs. All, except for one patient, were receiving supplemental oxygen. 6-min walking distance was mean±sd 340±84 m. Haemodynamic characteristics were: mean pulmonary artery pressure (PAP) 32±6 mmHg, cardiac index 3.5±1.1 L·min(-1)·m(-2) and pulmonary vascular resistance (PVR) 376±184 dyn·s·cm(-5). Mean PAP was >35 mmHg in only 20% of cases. The forced expiratory volume in 1 s was 42±25%, carbon monoxide transfer factor was 29±13%, and arterial oxygen tension (P(a,O(2))) was 7.4±1.3 kPa in room air. Mean PAP and PVR did not correlate with P(a,O(2)). In six patients who received oral pulmonary arterial hypertension (PAH) therapy, the PAP decreased from 33±9 mmHg to 24±10 mmHg and the PVR decreased from 481±188 dyn·s·cm(-5) to 280±79 dyn·s·cm(-5). The overall probability of survival was 94% at 2 yrs. Pre-capillary PH of mild haemodynamic severity may occur in patients with LAM, even with mild pulmonary function impairment. PAH therapy might improve the haemodynamics in PH associated with LAM.     

Successful treatment with sildenafil in systemic sclerosis patients with isolated pulmonary arterial hypertension: two case reports

We describe two systemic sclerosis (SSc) patients with isolated pulmonary arterial hypertension (PAH) who were given treatment with 50 mg oral sildenafil per day. We evaluated the efficacy of oral sildenafil for isolated PAH in SSc patients by direct assessment with cardiac catheterization before and 6 months after the initiation of sildenafil. Right-heart catheterization demonstrated decreased mean pulmonary artery pressure, decreased pulmonary vascular resistance, and increased cardiac output after treatment with sildenafil. Brain natriuretic peptide levels were gradually decreased. The 6-min walking distance was greatly extended. Moreover, the physical conditions of both patients were much improved. We recognized no adverse events. We propose that oral sildenafil may be beneficial as a selective pulmonary vasodilator and as long-term treatment in SSc patients with isolated PAH.     

Efficacy of oral sildenafil as rescue therapy in patients with severe pulmonary arterial hypertension chronically treated with prostacyclin. Long-term results

INTRODUCTION AND OBJECTIVE: Prostacyclin therapy is an effective treatment for severe pulmonary hypertension. Sildenafil, a selective phosphodiesterase type 5 inhibitor, induces selective vasodilatation of the pulmonary vessels. A synergistic effect has been described for these two drugs. The aim of this study was to evaluate the efficacy and safety of sildenafil as rescue therapy in patients with severe pulmonary hypertension on chronic treatment with prostacyclin whose clinical or functional course was unsatisfactory. PATIENTS AND METHOD: Observational study of 11 patients (7 men, 4 women, mean age 42 [8] years) diagnosed as having severe idiopathic pulmonary hypertension, who were receiving chronic prostacyclin therapy. Sildenafil was started after a worsening of their clinical or functional status. Baseline, 3-month and 12-month follow-up evaluations were based on functional status (NYHA functional class and 6-minute walking test), the presence of decompensated right heart failure and echocardiogram. RESULTS: Seven of the 11 patients showed significant improvements in exercise capacity (distance walked in 6 minutes) at 3 (+25 m) and 12 months' follow-up (+36 m). Improvements in functional class were seen, and heart failure disappeared. No significant adverse effects of sildenafil were detected. The echocardiographic parameters showed a significant reduction in right ventricular end-diastolic diameter and left ventricular diastolic eccentricity index. One patient died after 4 months of follow-up from sudden cardiac death. CONCLUSIONS: The addition of oral sildenafil to chronic prostacyclin treatment in patients with severe pulmonary hypertension improved functional capacity and reduced episodes of decompensated right heart failure, with good tolerance and no significant adverse effects.     

Chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease that results from obstruction of the major pulmonary arteries by incompletely resolved or organized pulmonary emboli that have become incorporated into the pulmonary artery wall, eventually causing an increase in pulmonary vascular resistance. From 0.1 to 4.0% of patients recovering from acute pulmonary embolism develop CTEPH. Without intervention, CTEPH is a progressive and lethal disease for which there is no effective medical therapy. Pulmonary endarterectomy (PEA) is the treatment of choice. Careful pre- and postoperative management is essential for a successful outcome after PEA. Lung transplantation is indicated only in few cases when PEA is not feasible. In 1994, we started a program (in Pavia, Italy) in which members of a multidisciplinary team work closely with the aim of increasing experience in the challenging problems these patients present in the evaluative, surgical, and postoperative phases of their care. To date, 134 PEAs have been performed. Preoperatively, New York Heart Association (NYHA) class distribution was three class II, 56 class III, and 75 class IV patients, respectively; mean pulmonary artery pressure and pulmonary vascular resistance values were 47 +/- 13 mm Hg and 1149 +/- 535 dyn/s/cm (-5), respectively. The overall operative mortality has been 9.7% (4.5% in 2004). Survival at 3-month, 1-year, and 3-year follow-up was 89.5 +/- 2.6%, 87.8 +/- 2.9%, and 83.3 +/- 3.5%, respectively; this last rate was unchanged up to 10 years. After PEA, mean pulmonary artery pressure and pulmonary vascular resistance values were 25 +/- 9 mm Hg and 322 +/- 229 dyn/s/cm (-5), respectively, and these results were stable over time. At the 3-year follow-up, 94% of patients were in NYHA class I or II and were being treated with oral anticoagulants only.     

Safety of sapropterin dihydrochloride (6r-bh4) in patients with pulmonary hypertension

The authors investigated the safety of oral tetrahydrobiopterin (BH4), a cofactor for nitric oxide synthesis, as a novel treatment for pulmonary hypertension (PH). Eighteen patients with pulmonary arterial hypertension or inoperable chronic thromboembolic PH received sapropterin dihydrochloride (6R-BH4), the optically active form of BH4, in addition to treatment with sildenafil and/or endothelin receptor antagonists in an open-label, dose-escalation study. 6R-BH4 was administered starting at a dose of 2.5 mg/kg and increasing to 20 mg/kg over 8 weeks. Changes in markers of nitric oxide synthesis, inflammation and oxidant stress, as well as exercise capacity and cardiac function were measured. 6R-BH4 was well tolerated at all doses without systemic hypotension, even when given in combination with sildenafil. There was a small but significant reduction in plasma monocyte chemoattractant protein (MCP)-1 levels on 5 mg/kg. No significant changes in measures of nitric oxide synthesis or oxidant stress were observed. There was improvement in 6-minute walk distance, most significant at a dose of 5 mg/kg, from 379 ± 61 to 413 ± 57 m 414 ± 57 m (P = .002). Oral 6R-BH4 can be administered safely in doses up to 20 mg/kg daily to patients with PH. Further studies are needed to explore its therapeutic potential.     

Thoracic research scholarship 1988: pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension at the University of California, San Diego

At the University of California, San Diego pulmonary thromboendarterectomy (PTE) has emerged as an effective measure in the treatment of chronic thromboembolic pulmonary hypertension. Unresolved emboli become organized by incorporation into the vascular wall and may form strictures, webs, bands and/or membranous occlusions and cause pulmonary hypertension refractory to medical treatment. When pulmonary vascular resistance exceeds 300 dyn.sec.cm-5 and the vascular wall changes are located to begin at or proximal to the lobar artery level, surgery is indicated. The operation is performed using cardiopulmonary bypass, deep hypothermia and periods of circulatory arrest. The dissection of each segmental artery is carried out in the media layer from separate incisions in the right and left pulmonary artery at the level of the pericardial flexion. Pulmonary reperfusion edema may complicates the postoperative course, and pulmonary hemorrhage, respiratory insufficiency necessitating prolonged ventilatory support and secondary multi organ failure are main causes of hospital mortality. Between October 1984 and September 1988 103 patients with a mean age of 50 +/- 16 years underwent PTE. Consequently, pulmonary vascular resistance could be reduced from 788 +/- 370 to 299 +/- 150 dyn.sec.cm-5 and cardiac index increased from 2.0 +/- 0.6 to 3.2 +/- 0.8 l/min-m2. Hospital mortality was 11.7% (12/103 patients). Thus, pulmonary thromboendarterectomy effectively reduces pulmonary hypertension at an acceptable low risk. The results indicate that patients should be diagnose and referred for surgery as early as possible.     

Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension

OBJECTIVES: To evaluate the effect of long-term oral therapy with sildenafil in patients with pulmonary arterial hypertension receiving long-term IV epoprostenol. DESIGN: Open, uncontrolled trial. SETTING: University hospital. PATIENTS: Two patients with primary pulmonary hypertension and one patient with pulmonary arterial hypertension after surgical closure of an atrial septal defect. All patients were receiving continuous epoprostenol for 1.7 to 7.1 years; two patients also received inhaled iloprost for 1.8 years and 3.8 years, respectively. INTERVENTIONS: Addition of oral sildenafil, up to 200 mg/d, divided in four to six single doses, and hemodynamic measurements and the 6-min walking distance (6MWD) before and after 5 months of treatment with sildenafil. RESULTS: One patient was treated with sildenafil, 200 mg/d; two patients received 75 mg/d due to nausea and headache. Long-term treatment with sildenafil in the three patients reduced mean pulmonary artery pressure by 14%, 41%, and 22%, respectively; in two patients, pulmonary vascular resistance was decreased by 52% and 55%. The 6MWD increased by 34%, 6%, and 29%, respectively. No significant systemic hypotension or decrease of arterial oxygen saturation was seen. CONCLUSION: Sildenafil therapy may be of benefit in patients with pulmonary arterial hypertension receiving long-term infusion of epoprostenol.     

Intravenous iloprost for treatment failure of aerosolised iloprost in pulmonary arterial hypertension.

Treatment with aerosolised iloprost, a prostacyclin analogue, has beneficial effects in patients with pulmonary arterial hypertension (PAH). It is unclear if patients, whose clinical condition deteriorates under treatment with aerosolised iloprost, benefit from switching to continuous intravenous iloprost. The current authors report on 16 patients with severe PAH who received continuous intravenous iloprost after primary or secondary failure of treatment with aerosolised iloprost. Determinants of efficacy were survival, New York Heart Association (NYHA) class, and walking distance in the 6-min walk test. Of 93 patients with PAH treated with aerosolised iloprost, 16 required switching to intravenous iloprost for clinical deterioration. These patients had severe right heart failure with a cardiac index of 1.6+/-0.2 L x min(-1) x m(-2) and a mixed-venous oxygen saturation of 52+/-6%. Five of these patients showed no improvement and eventually died. Three patients had further deterioration in NYHA class and exercise capacity; two of them underwent lung transplantation; the third patient is still alive. Eight patients showed marked clinical improvement; one underwent lung transplantation and the others are currently alive and stable. In the latter group of patients, the walking distance in the 6-min walk test increased from 205+/-94 to 329+/-59 m. It was not possible to identify clinical or haemodynamic factors that would predict whether switching from inhaled to intravenous iloprost would have a beneficial effect. In patients with pulmonary arterial hypertension who deteriorated while being treated with aerosolised iloprost, switching to continuous intravenous iloprost caused substantial improvement in exercise capacity in eight of 16 patients but could not prevent progression of pulmonary hypertension in the remaining eight patients. Since it was impossible to predict the individual effects of this approach, intravenous prostaglandin treatment should be considered in pulmonary arterial hypertension patients who deteriorate while receiving iloprost aerosol.